Abstract
The benefits of chronic hepatitis C viral (HCV) cure on various aspects of patients’ health experiences may be under-appreciated. The aim of this study was to conduct an in-depth evaluation of change in a comprehensive set of patient-reported symptoms and aspects of life functioning after achieving HCV cure using validated instruments. Patients completed the 32-item Memorial Symptom Assessment Scale (MSAS) and several Patient-Reported Outcomes Measurement Information System® (PROMIS®) measures prior to DAA treatment and up to 10 months after viral cure. Pre- and post-MSAS scores for all 32 individual symptoms, three subscales, and a total symptom score, and several PROMIS T-scores were compared. The total MSAS score, Physical subscale and Psychological subscale scores all improved by 28 to 33% (p<0.01) and numerous previously unidentified HCV-associated symptoms improved by 30 to 100% from baseline scores. Significant improvements in gastrointestinal, mood, sleep, fatigue, and cognition concerns, as well as stigma were observed using the PROMIS measures by 5 to 11%. Improvements in previously unidentified symptoms, stigma, and other aspects of life functioning provide additional support for the substantial personal benefits bestowed upon individuals who are cured of HCV, and support health policy, payer, and pharmaceutical decisions to ubiquitiously treat all people infected with this life-impairing infectious disease.
Keywords: hepatitis C virus, antiviral agents, health-related quality of life, pain, fatigue
INTRODUCTION
Chronic hepatitis C virus (HCV) has been associated with multiple symptoms, poor quality of life (QOL), and impaired life functioning.1,2 Recently, a large real-world observational study found significant improvements in fatigue, sleep disturbance, and functional well-being in patients who achieved sustained virologic response (SVR).3 Patients may experience other subjective benefits from SVR that are not well-documented, such as improvements in lesser-known symptoms, self-perception, emotional and psychological well-being, and social and romantic relationships.4 It is important to identify the full range of symptoms and aspects of life functioning that improve after viral cure to realize the holistic benefits of direct-acting antiviral (DAA) therapy bestowed upon patients’ lives.5 The aim of this study was to evaluate changes in numerous symptoms and aspects of QOL, some not previously well-described, from before DAA therapy to several months after treatment to provide in-depth comprehensive documentation of numerous benefits following viral cure.
METHODS
Study Design and Population
This was a pre-post observational cohort study conducted from 2017–2018. Patients initiating sofosbuvir-based treatment for chronic HCV were recruited from an outpatient hepatology clinic. Participants were age ≥ 21 years and English-speaking. Liver transplant candidates or recipients were excluded. Pre-treatment PRO assessments were completed before DAA therapy began and post-treatment assessments were completed 4 to 10 months after treatment in patients who achieved SVR. The study was approved by the local IRB and patients consented before participation.
Data Collection and Measures
Patient and Treatment Characteristics.
Participants completed a brief sociodemographic survey prior to treatment. Cirrhosis status, HCV genotype, prior treatment, treatment regimen and duration, and SVR status were extracted from electronic medical records. Presence or absence of cirrhosis was based on results of FibroSure, FibroScan, or liver biopsy, or determined by a hepatologist’s clinical judgment based on radiographic studies, laboratory values, or physical exam.
Memorial Symptom Assessment Scale (MSAS).
The MSAS is a validated instrument that evaluates a comprehensive set of 32 symptoms commonly associated with most chronic medical conditions or treatments and has satisfactory psychometric properties.6 Participants first indicate the presence or absence of each symptom in the past week, and if present, the symptom is rated on three dimensions: frequency, severity, and distress. In addition to evaluating change in each of the 32 symptoms, we also evaluated change in the (1) Total MSAS score (TMSAS), a composite of overall symptom burden score, (2) Physical Symptom Subscale score (MSAS-PHYS), (3) Psychological Symptom Subscale score (MSAS-PSYCH), and (4) Global Distress Index (MSAS-GDI). Scores ranged from 0 to 4, with higher scores representing worse symptoms.
PROMIS Short Form Measures.
The Patient-Reported Outcomes Measurement Information System® (PROMIS®) includes measures of symptoms and life functioning with extensive evidence for its reliability and validity across a broad range of chronic conditions, including HCV.7 We used PROMIS short forms to measure the following domains: (1) symptoms of depression, anxiety, anger, fatigue, cognitive concerns, sleep disturbance, pain, nausea, diarrhea, abdominal pain, (2) physical functioning, and (3) social functioning such as satisfaction with sexual activity, social isolation, and ability to participate in social roles/activities. Higher PROMIS scores reflect more of the domain being measured; thus, higher symptom scores reflect worse symptoms but higher function scores reflect better functioning. Internalized stigma was measured using the Neuro-QoL™ 6-item Stigma instrument.
Statistical Analysis
For each MSAS symptom, the proportion of participants who reported the presence of the symptom pre- and post-treatment is reported. Among participants who reported the presence of a symptom at baseline, pre- and post-treatment mean scores, mean change scores with 95% confidence intervals (95% CIs), and mean percent change scores from baseline are reported. Pre- and post TMSAS, MSAS-PHYS, MSAS-PSCYH, and MSAS-GDI scores for the entire cohort were compared using paired t-tests. For the PROMIS instruments, pre-post T-scores, mean change scores with 95% CIs, and mean percent change scores are reported. Pre-post T-scores were compared using paired t-tests. Significance for t-tests was set at α=0.05. A change in T-score of 2 to 5 points is often considered a minimal clinically important difference.8 Statistical analyses were conducted using STATA v15.1 (STATACorp, College Station, TX).
RESULTS
Baseline Characteristics
The study included 89 participants with a median age of 57 years (range 24–69), 51% female, and 66% White. The majority of participants had up to a high school education (60%); household income was less than $40,000 per year (86%), and about half were uninsured. The majority (96%) were treatment naïve, 29% had cirrhosis, and 64% were treated with ledipasvir/sofosbuvir.
Change in Symptoms and Total Symptom Burden based on the Memorial Symptom Assessment Scale
According to the MSAS, substantial reductions in the proportions of participants experiencing many symptoms, such as lack of energy, worrying, difficulty sleeping, feeling sad, and nausea, were observed after viral cure (Table 1). Among participants who reported a symptom pre-treatment, the average severity, frequency, and distress of these symptoms reduced after viral cure, with mean percent change from 21% to 100%. Among the five most common symptoms reported prior to HCV treatment (i.e., lack of energy, pain, worrying, difficulty sleeping, and numbness/tingling in the hands/feet), post-treatment scores decreased, on average, by 37% to 55%, compared to baseline.
Table 1.
Proportion of participants with pre- and post-treatment symptoms and pre- and post-treatment scores
| MSAS symptoms | Presence of symptom pre-treatment (%) | Presence of symptom post-treatment (%) | Pre-treatment mean score a | Post-treatment mean score a | Mean change score (95% CI) | Mean % change score |
| Lack of energy | 68.5 | 40.5 | 2.75 | 1.23 | −1.52** (−1.87, −1.17) |
−55.3 |
| Pain | 62.9 | 49.4 | 2.87 | 1.82 | −1.04** (−1.38, −0.70) |
−36.6 |
| Worrying | 58.4 | 36.0 | 2.61 | 1.31 | −1.31** (−1.73, −0.89) |
−49.8 |
| Difficulty sleeping | 57.3 | 38.2 | 2.84 | 1.53 | −1.31** (−1.70, −0.91) |
−46.1 |
| Numbness/tingling in hands/feet | 47.2 | 44.9 | 2.56 | 1.62 | −0.94** (−1.40, −0.49) |
−36.7 |
| Feeling drowsy | 44.9 | 31.5 | 2.36 | 1.01 | −1.35** (−1.72, −0.98) |
−57.2 |
| Feeling nervous | 42.7 | 30.3 | 2.45 | 1.14 | −1.30** (−1.72, −0.89) |
−53.5 |
| Feeling sad | 42.7 | 27.0 | 2.43 | 1.16 | −1.27** (−1.80, −0.74) |
−52.3 |
| Cough | 42.7 | 28.1 | 2.06 | 0.98 | −1.08** (−1.48, −0.68) |
−52.4 |
| Dry mouth | 40.5 | 30.3 | 2.42 | 1.04 | −1.38** (−1.81, −0.96) |
−57.0 |
| Difficulty concentrating | 39.3 | 29.2 | 2.25 | 0.82 | −1.43** (−1.72, −1.14) |
−63.6 |
| Feeling irritable | 38.2 | 25.8 | 2.63 | 0.95 | −1.67** (−2.15, −1.19) |
−63.9 |
| Sweats | 38.2 | 23.6 | 2.56 | 0.86 | −1.71** (−2.14, −1.28) |
−66.4 |
| Feeling bloated | 32.6 | 22.5 | 2.63 | 1.18 | −1.45** (−2.08, −0.82) |
−55.1 |
| Nausea | 31.5 | 15.7 | 2.11 | 0.45 | −1.66** (−2.08, −1.25) |
−78.7 |
| Shortness of breath | 30.3 | 20.2 | 2.19 | 1.19 | −1.00** (−1.49, −0.52) |
−45.7 |
| Itching | 29.2 | 19.1 | 2.69 | 1.12 | −1.57** (−2.17, −0.97) |
−58.4 |
| Lack of appetite | 28.1 | 21.4 | 2.56 | 0.72 | −1.84** (−2.44, −1.25) |
−71.9 |
| Problems with sexual interest or activity | 24.7 | 20.2 | 2.84 | 1.06 | −1.78** (−2.48, −1.08) |
−62.7 |
| Dizziness | 23.6 | 18.0 | 2.36 | 0.80 | −1.56** (−2.10, −1.03) |
−66.1 |
| Swelling of arms or legs | 20.2 | 24.7 | 2.11 | 1.67 | −0.44 (−1.08, 0.20) |
−20.9 |
| “I don’t look like myself” | 20.2 | 9.0 | 2.44 | 0.44 | −2.00** (−2.44, −1.56) |
−82.0 |
| Diarrhea | 19.1 | 15.7 | 2.29 | 0.91 | −1.38** (−2.00, −0.76) |
−60.3 |
| Constipation | 19.1 | 13.5 | 2.31 | 0.45 | −1.86** (−2.43, −1.28) |
−80.5 |
| Problems with urination | 18.0 | 11.2 | 2.64 | 1.22 | −1.42** (−2.22, −0.63) |
−53.8 |
| Weight loss | 18.0 | 15.7 | 1.94 | 0.30 | −1.64** (−2.19, −1.10) |
−84.5 |
| Changes in skin | 14.6 | 10.1 | 2.81 | 0.65 | −2.16** (−2.95, −1.37) |
−76.9 |
| Change in the way food tastes | 9.0 | 10.1 | 2.25 | 0.90 | −1.35** (−2.36, −0.34) |
−60.0 |
| Difficulty swallowing | 9.0 | 5.6 | 1.82 | 0.69 | −1.13** (−1.93, −0.32) |
−62.1 |
| Hair loss | 9.0 | 5.6 | 1.91 | 0.93 | −0.99** (−1.88, −0.09) |
−51.3 |
| Vomiting | 3.4 | 4.5 | 1.76 | 0 | −1.76** (−2.23, −1.28) |
−100.0 |
| Mouth sores | 2.3 | 3.4 | 2.20 | 0 | −2.20 (−7.28, 2.88) |
−100.0 |
| MSAS subscales | Presence of symptom pre-treatment (%) | Presence of symptom post-treatment (%) | Pre-treatment mean score | Post-treatment mean score | Mean change score (95% CI) | Mean % change score |
| Total MSAS | -- | -- | 0.74 | 0.53 | −0.21** (−0.33, −0.10) |
−28.4 |
| MSAS-PHYS | -- | -- | 0.84 | 0.56 | −0.28** (−0.43, −0.14) |
−33.3 |
| MSAS-PSYCH | -- | -- | 1.18 | 0.79 | −0.39** (−0.61, −0.17) |
−33.1 |
| MSAS-GDI | -- | -- | 1.19 | 0.79 | −0.40** (−0.60, −0.21) |
−33.6 |
| PROMIS domain | Presence of symptom pre-treatment (%) | Presence of symptom post-treatment (%) | Pre-treatment mean T-score | Post-treatment mean T-score | Mean change T-score (95% CI) | Mean % change T-score |
| Belly pain | -- | -- | 47.73 | 42.37 | −5.36** (−8.52, −2.20) |
−11.2 |
| Nausea/vomiting | -- | -- | 48.78 | 44.83 | −3.95** (−6.00, −1.90) |
−8.1 |
| Depression | -- | -- | 52.58 | 48.85 | −3.73** (−6.06, −1.40) |
−7.1 |
| Sleep disturbance | -- | -- | 53.53 | 50.16 | −3.37** (−5.83, −0.91) |
−6.3 |
| Anger | -- | -- | 52.03 | 48.70 | −3.33** (−6.03, −0.63) |
−6.4 |
| Fatigue | -- | -- | 53.56 | 50.26 | −3.30** (−5.92, −0.68) |
−6.2 |
| Anxiety | -- | -- | 52.66 | 50.66 | −2.01 (−4.32, 0.30) |
−3.8 |
| Cognitive concerns | -- | -- | 34.64 | 32.65 | −1.99** (−3.95, −0.02) |
−5.7 |
| Diarrhea | -- | -- | 47.14 | 46.12 | −1.02 (−3.09, 1.05) |
−2.2 |
| Pain interference | -- | -- | 54.16 | 53.51 | − 0.65 (−3.21, 1.91) |
−1.2 |
| Physical functioning | -- | -- | 47.44 | 45.80 | −1.64 (−3.71, 0.43) |
−3.5 |
| Stigma† | -- | -- | 46.91 | 44.57 | −2.34** (−4.05, −0.63) |
−5.0 |
| Social isolation | -- | -- | 44.08 | 43.47 | −0.62 (−2.59, 1.36) |
−1.4 |
| Ability to participate in social roles and activities | -- | -- | 52.76 | 52.67 | −0.10 (−2.35, 2.16) |
−0.2 |
| Satisfaction with sexual activity | -- | -- | 54.78 | 55.24 | +0.46 (−3.17, 4.09) |
+0.8 |
Scores among participants who reported the presence of each symptom at baseline.
Represents mean change scores that are statistically significant at p<0.05.
Note: Neuro-QoL measure.
Significant reductions in mean change scores were also observed for total symptom burden (TMSAS score) and the three subscales. Compared to baseline, TMSAS decreased by 28%, MSAS-PHYS decreased by 33%, MSAS-PSYCH decreased by 33%, and GDI decreased by 34% (all p-values <0.01).
Change in Symptoms, Life Functioning and Stigma based on PROMIS and Neuro-QoL Measures
Statistically significant improvements in several physical and mental symptoms were observed. The greatest improvement was reported for belly/liver pain with an average T-score reduction of 5.36 points (95% CI 2.20 to 8.52, p<0.01), followed by a reduction in nausea by 3.95 points (95% CI 1.90 to 6.00, p<0.01) and depressive symptoms by 3.73 points (95% CI 1.40 to 6.06, p<0.01) (Table 1). Statistically significant reductions in sleep disturbance, fatigue, cognitive concerns, and anger were also observed with an average T-score reduction ranging from 2.0 to 3.4 points. While improvements were observed in Physical Functioning, these changes did not reach statistical significance. Three measures of social functioning (i.e., social isolation, social participation, and satisfaction with sexual activity) did not significantly improve; however, perceptions of stigma did substantially improve after viral cure (mean change score 2.34 [95% CI 0.63 to 4.05] p<0.01).
DISCUSSION
Participants experienced significant improvements in most physical and psychological symptoms, and also had significant improvements in overall symptom burden and global distress related to the presence of symptoms. Symptom improvements reflected by the PROMIS measures were found to be consistent with the results from the MSAS; both noting substantial improvements in patients’ energy, pain, sleep, nausea, cognition, and mood. Significant reductions in depressive symptoms and feelings of stigma were reported after viral cure; these are common experiences of people living with HCV that can have profound benefits on multiple aspects of life functioning.2 These findings are consistent with, but expand upon the existing literature by documenting additional symptoms that improve following viral cure.
Importantly, our study documents improvements in several individual symptoms using the MSAS that are not well-documented in the extant literature. Between 25% and 50% of the sample reported pre-treatment numbness/tingling, cough, dry mouth, sweats, bloating, and itch. While these symptoms are not commonly reported by patients with HCV, it is certainly biologically plausible that viral elimination could improve these symptoms given that HCV is a chronic inflammatory virus that taxes the immune and central nervous systems even in the absence of liver disease. Using the PROMIS measures, there were also significant reductions in gastrointestinal symptoms such as belly pain, nausea and vomiting, as well as sleep, anger, fatigue, and cognitive concerns.
This study is limited by the relatively small sample size and recruitment from a single center. Despite these limitations, this study conducted an in-depth analysis of an extensive number of symptoms that are potentially ameliorated following viral cure. This study is the first to explore 32 individual symptoms from the MSAS and several novel measures related to social functioning including social isolation, stigma, and sexual satisfaction. Finally, this study reflects the real-world experiences of people treated with DAAs and is less subject to some of the biases inherent in registration trials.
This study provides a comprehensive evaluation of the profound benefits bestowed upon patients who are given the opportunity to achieve HCV viral eradication. These findings expand upon the existing literature by demonstrating how successful antiviral therapy can result in life-changing improvements in numerous previously unidentified symptoms that may be less prevalent in the chronic HCV population, yet certainly bothersome to those living with a virus that can affect the nervous and immune systems. With future psychometric testing, the MSAS and PROMIS measures may be considered worthwhile instruments to evaluate patient-centered outcomes that complement traditional efficacy and safety end points of new antiviral medications. This study provides a deeper understanding of novel benefits to patients that can enhance patient-provider communication, treatment decision-making, and health policy to advance the treatment of all people infected with chronic HCV.
Acknowledgements:
This research was funded by Gilead Sciences, Inc. Additional support for this project was funded, in part, by a grant from the National Institutes of Health (T32 DK007634), the NIDDK-funded Center for Gastrointestinal Biology and Disease (CGIBD; PI: Sandler; P30-DK34987), and the National Center for Advancing Translational Sciences (NCATS; UL1TR002489) for the North Carolina Translational and Clinical Sciences Institute.
Conflicts of Interest: Donna M. Evon has grant funding from Merck, Sharp and Dohme, paid to the University of North Carolina. Hannah P. Kim, Angela Edwards, Bryce B. Reeve, and Carol E. Golin have no financial interests to disclose.
Abbreviations:
- HCV
chronic hepatitis C
- DAA
direct-acting antiviral
- PRO
patient-reported outcome
- HRQOL
health-related quality of life
- SVR
sustained virologic response
- MSAS
Memorial Symptom Assessment Scale
- TMSAS
total MSAS
- MSAS-PHYS
Physical Symptom Subscale
- MSAS-PSYCH
Psychological Symptom Subscale
- MSAS-GDI
Global Distress Index
- PROMIS
Patient-Reported Outcomes Measurement Information System
Data Availability Statement:
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.